EP1363593A1

EP1363593A1 - Free nicotine based cosmetic composition and uses thereof

Info

Publication number: EP1363593A1
Application number: EP02704862A
Authority: EP
Inventors: Patrick Maillon
Original assignee: COLUMBUS
Current assignee: COLUMBUS
Priority date: 2001-02-26
Filing date: 2002-02-19
Publication date: 2003-11-26
Also published as: FR2821270A1; US20040037860A1; WO2002067891A1; FR2821270B1

Abstract

A topical cosmetic composition comprising nicotine mixed with at least one cosmetically acceptable excipient, characterized in that the nicotine is free nicotine. The inventive cosmetic composition can especially be used in the treatment of cellulitis.

Description

COSMETIC COMPOSITION BASED ON FREE NICOTINE AND USES

The subject of the invention is a composition based on free nicotine. It also relates to the use of said composition for reducing or eliminating any localized fatty overload of the cellulite type in particular. Finally, it relates to the cosmetic treatment of cellulite by local application of said cosmetic composition.

What is called cellulite in common parlance is localized gynoid lipodystrophy (here called LGL), harmless to health but with aesthetic repercussions. When there is an imbalance between the intake of fat and its use by the body, the adipocytes overfill with lipids and compress the neighboring blood and lymphatic vessels, leading to poor drainage. Then there is water retention. The thighs full of fat and water become partitioned by a gangue made up of elements of the fundamental substance and more especially of proteoglycans which are polymeric substances. These inelastic partitions constitute, on the surface of the skin, so-called “orange peel” dents, which are painful when pinched, because the nerve nets are pulled by the adipose tissue.

Localized gynoid lipodystrophy (LGL) is an abnormal process of fatty accumulation in the fat cells of the thighs, and has among other determinants, hormonal dependence. Estrogens promote this accumulation, so at the time of puberty, pregnancy or menopause, hormonal changes in the body often induce the development of fatty tissue. There is also a family or ethnic character. When LGL remains for a long time, it can become indurated, distended tissues becoming fibrous, and becomes more difficult to treat, see "Giudicelli Y. - Physiology of adipose tissue (recent data). Cosmetology 1995; 5: 46-49." LGL is an extremely common feature in women in Europe and North America.

The classic treatment is based on local techniques based on massages and drainage, whose effectiveness is limited, or even liposuction or liposuction in difficult cases. But liposuction is especially interesting when the LGL is mainly adipose, not very organized.

Processes based on mechanical massages, electrical stimulation (electrolipolysis) or ultrasound have also been developed.

The use of enzymes aimed at depolymerizing proteoglycans have been proposed, in particular hyaluronidase, thiomucase and Foc-mucase.

Methods for stimulating lipolysis have also been proposed, the best known and most used being that which consists of inhibiting phosphodiesterase in order to limit the rate of degradation of cyclic AMP. The activation of cyclic AMP intervenes in the lipolytic activity of the adypocyte. Among the various phosphodiesterase inhibitors which have been recommended as weight loss agents, mention may in particular be made of xantics and more particularly theophyline, caffeine and theobromine.

Document US-A-4,938,962 describes for example a cosmetic composition intended for the treatment of cellulite comprising the combination of thioether with xanthine derivatives of the aforementioned type. As thioether, the possible use of 2-benzylthioethylamine in the form of a salt, for example nicotinate, is mentioned.

Document US-A-4,938,962 describes a cosmetic composition for the treatment of cellulite combining a metal salt of caffeine with vitamin E. In the same vein, it has been recommended the use of certain oil-soluble plant extracts which, according to a different mechanism, can also act as weight loss agents. Among these plant extracts one can mention those of the type, climbing ivy, arnica, rosemary, marigold, sage, ginseng, St. John's wort, fragon, ulmaire and orthosiphon as well as mixtures of such plants.

Document DE4461308 thus describes an anticellulitic composition associating a plant extract and an activator of the metabolism of the vitamin E type in the form of salt, in particular of nicotinate and with a draining active.

Despite the multitude of cosmetic techniques or compositions proposed today, none is completely satisfactory. The Applicant therefore sought to develop new solutions to the problem posed of the fight against cellulite. In this context, he discovered that free nicotine, that is to say nicotine base had, quite surprisingly, anticellulitic effects or more generally was capable of reducing or eliminating any localized fat overload. In addition, the Applicant has found that free nicotine improves on the one hand, the firmness and on the other hand, the softness of the epidermis and that in addition it delays skin aging.

Free nicotine has been used for many years in smoking cessation, since the nicotine contained in tobacco smoke leads to real physical dependence, the brutal withdrawal of which gives rise to serious mental and physical disorders. Consequently, free nicotine is incorporated into topical pharmaceutical compositions of the patch or oral type, of the chewing gum or oral lozenge type. Free nicotine can also be administered transmucosally using, for example, a nasal spray. Whatever the type of drugs used, the objective of smoking cessation is to deliver a sufficient amount of free nicotine in the brain and in the system as a whole for said withdrawal to be effective while being controlled. This is the reason why it is imperative to deliver a relatively large amount of nicotine continuously or at regular intervals, from 14 to 21 mg / 24 hours, or even more in certain cases of strong dependence on nicotine. These doses are then reduced to finalize weaning.

Even if certain prior art documents, in particular documents US-A-4,938,962 and DE-440308 describe the use of nicotine for the treatment of cellulite, they are systematically nicotine derivatives used in the form of salts, in particular nicotinate. Also, nothing in these documents suggested to a person skilled in the art to use, instead of salts, free nicotine, that is to say nicotine base.

It was therefore not obvious, with regard to the state of the art known to those skilled in the art, that free nicotine could be used in the field of cosmetics, in particular for the treatment of cellulite.

The subject of the invention is therefore a topical cosmetic composition comprising nicotine in admixture with at least one cosmetically acceptable vehicle, which is characterized in that the nicotine is free nicotine.

According to a first characteristic of the invention, the free nicotine represents between 0.001 and 0.5% by weight of the composition.

For a value less than 0.001, there is no convincing effect. For a value greater than 0.5%, there is a risk of significant systemic passage of free nicotine. The topical composition of the invention is used in local application and can therefore be in various forms such as gel, oily gel, cream, ointment, milk, lotion, balm, spray, emulsion, patch, stick.

When the composition is an emulsion, the proportion of the fatty phase can range from 5% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the composition. The oils, waxes, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the cosmetic field. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

In a known manner, the cosmetic composition may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, odor absorbers and coloring matters. The amounts of these various adjuvants are those conventionally used in the cosmetic field, and for example from 0.01% to 10% of the total weight of the composition.

As oils or waxes which can be used in the invention, mention may be made of mineral oils, vegetable oils, animal oils, synthetic oils, silicone oils or waxes and beeswax, carnauba or paraffin waxes. Fatty alcohols and fatty acids (stearic acid) can be added to these oils.

As solvents which can be used in the invention, mention may be made of lower alcohols, in particular ethanol and isopropanol, propylene glycol.

As hydrophilic gelling agents which can be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, ethylcellulose, polyethylene

As already said, the Applicant has discovered that free nicotine acts on cellulite, firmness, smoothness and aging of the skin.

Consequently, the invention also relates to the use of the composition as described above, for reducing or limiting any localized fatty overload, of the cellulite type in particular.

It is obvious that in no case can this use be considered as corresponding to a therapeutic treatment since the local application of free nicotine is not intended to avoid a pathological condition but on the contrary to improve a state of purely aesthetic order.

The use of free nicotine is also planned for the manufacture of a composition intended to reduce or limit any localized fatty overload, of the cellulite type in particular.

The invention also relates to the use of the cosmetic composition described above for increasing the firmness of the epidermis. This property is particularly advantageous for the treatment of wrinkles.

Likewise, it relates to the use of the composition described above for combating skin aging.

According to another aspect, it relates to the use of the composition described above to improve the smoothness of the epidermis. The invention also relates to a method of cosmetic treatment of local fatty overloads of the cellulite type in particular, according to which a locally effective amount of the composition described above is applied topically.

In practice, the amount of nicotine released does not exceed 5 mg per application, it is advantageously between 0.3 and 3 mg.

The invention and the advantages which result therefrom will emerge clearly from the following examples of embodiment.

Example 1: Comparative test

1 / INTRODUCTION

The Applicant has carried out a comparative trial intended to assess the effectiveness of the composition of the invention, in local topical application, in patients with gynoid lipodystrophy of the thighs and buttocks, in comparison with a placebo, considered as a control group. Concomitantly, the effects of the composition on the softness and firmness of the skin have been appreciated.

The dose of nicotine delivered through the skin is from 0.5 mg per ^'side (thigh and buttocks), facing areas of LGL, with two applications per day for 56 days. The formulas of the compositions applied are the following:

2 / METHOD

2.1 / Objectives of the study

The objectives of this clinical trial, performed in patients with gynoid lipodystrophy of the thighs and buttocks are as follows:

main objective: compare the effectiveness of the composition of the invention compared to a placebo topical, secondary objective: assess the development of tolerance of LGL; as well as the satisfaction, the local, general, clinical and biological tolerance of the product, and in particular its safety. Evaluate the softness and suppleness of the skin, its firmness, the reduction in the number and depth of the dimples. 2.2 / Profile of the study

This is a single-center, double-blind, comparative, randomized trial comprising two treatment groups for localized gynoid lipodystrophy of the thighs and buttocks (LGL):

Group 1: treatment with the composition of the invention (verum). Group 2: treatment with a percutaneous placebo topical

This trial lasted 9 weeks and included a one-week inclusion phase, followed by an 8-week treatment phase. It has been performed in patients suffering from LGL.

The total number of patients in this preliminary study is 40.

2.3 / Efficiency criteria

Evaluation carried out during the inclusion visit, on D28, and at the final visit for the main and secondary criteria.

2.3.1 Main criterion

1. - Measurement of the adipose panicle by ultrasound, measured using a wide probe, opposite the greater trochanter of each femur. "Diridollou S. Gall Y. -

Ultrasound exploration of the skin: promising beginnings. Cosmetology 1998; 17: 40-45 ",." Ohnuma M., Ashi∑awa K. - A-Mode Type Ultrasonique and Caliper Measurments of Subcutaneous Adipose Tissue Thickness. J. Human Zrgol, 1988; 17: 97-100 "," Schnebert S, Perin F., ^' Pittet J.-C, Beau P., Pourcelot Léandre - Ultrasound, an accessible and reliable technique to measure the effectiveness of slimming products. Cosmetology 1999; 22: 35-38 ”.

2. The probe was placed on a tripod, at constant height from the ground for each subject. The measurement was made after acquisition of the last possible image by detaching the probe from the skin plane.

2.3.2 Secondary criteria

- Subjective assessment of the patient on the evolution of her LGL, evaluated by analog visual scales.

- Evolution of the patient's subjective tolerance to her LGL, assessed by analog visual scales.

- Subjective appreciation of the patient on the evolution of the firmness of her skin, the number and depth of the dimples, by visual analog scale.

- Assessment of the suppleness and softness of the skin by daily monitoring sheet.

2.4 / Acceptability

- Average overall satisfaction with LGL treatment in patients in groups 1 and 2, evaluated during the final visit and measured with a visual analog scale coding satisfaction from 1 to 15.

- Discomfort caused by the treatment on daily activity, evaluated during the final visit, and qualified as mild (not affecting daily activity), moderate (not greatly affecting daily activity, but requiring more rest during the day), severe (affecting daily activity, requiring prolonged bed rest). 2.5 / General tolerance

The assessment of general tolerance was carried out during the final visit. A biological assessment was carried out during the selection visit and the final visit (blood count, platelet count, ALAT and ASAT transaminases).

2.6 / Satisfaction

Patient satisfaction in both groups was assessed through a question on the rate of product recommendation by visual analog scale.

3 / CRITERIA OF INCL USION AND NON-INCL USION

3.1 / Inclusion criteria

- Woman aged at least 18, - Patient suffering from LGL,

- Patient wishing to see her LGL reduced, and agreeing to submit to the conditions of treatment and protocol,. •

- Patient whose body mass index is less than 30, (EVIC = P / T2),

- Patient who does not consume, and who has never regularly used tobacco, in whatever form (cigarette, cigar, pipe, quid, socket, etc.),

- Patient free of a cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological or neurological affection determined by the anamnesis or by the clinical examination, - Patient likely not to be pregnant during the test. 3.2 / Non-inclusion criteria

- Patient with a history of hypersensitivity to nicotine and to the other constituents of the studied product, - Patient using or having used a nicotinic product (transdermal device, chewing gum, spray etc.) for less than two years,

- Patient with or having had morbid obesity with a body mass index greater than 30,

- Patient having presented a serious affection requiring treatment or continuous monitoring,

- Patient presenting or having presented a cutaneous affection - with or without systemic repercussions,

- Participation in another clinical trial in the 3 months preceding this trial, - Patient whose biological selection assessment is not within the limits of the standards set by NF, SGOT, SGPT),

- Patient having undergone recent surgery,

- Patient who, in the opinion of the experimenter, would not be able to follow the prescriptions of the protocol.

4 / RESULTS

All the results presented here include the entire population having followed the complete protocol.

Number of patients: 40 patients randomized to a single center, 20 received nicotinic gel treatment and 20 received placebo gel. 4.1 / Demographic criteria

They are similar in the two groups of 20:

Table 1: demographic criteria and characteristics at inclusion

Verum placebo Total

Average Age (standard deviation) 40.683 (8.955) 41, 408 (9.965) 41.046 (9.358) Minimum 21.3 18.3 18.3 Maximum 53.2 52.8 53.2

Average weight (standard deviation) 65,950 (6,646) 66,235 (9,659) 99,092 (8,133) Minimum 57 48.8 48.8 Maximum 80.5 85.5 85.5

BMI Average (standard deviation) 25,186 (2,301) 25,331 (3,217) 25,259 (2,762) Minimum 21.5 19.5 19.5 Maximum 29 29.9 29.9

LGL thickness measured on both thighs Average (standard deviation) 90.44 (16.62) 86.61 (30.32) 88.53 (24.21) Minimum 63.4 33.0 33 ^• Maximum 124.2 142 , 8,142.8

Perimeter of both thighs (bottom) Average (standard deviation) 99.57 (6.99) 99.62 (7.62) 99.60 (7.22) Minimum 87.5 85.5 85.5 Maximum 1 18, 0 1 14.5 1 18.0

Perimeter of both thighs (top) Average (standard deviation) 1 18.88 (7.70) 1 17.50 (9.16) 118.19 (8.38) Minimum 107.5 99.5 99.5 Maximum 137 139 139

Bitrochanteric perimeter

Mean (standard deviation) 102.00 (4.87) 102.53 (7.05) 102.26 (5.99)

Minimum 94.0 90.0 90.0

Maximum 1 12.5 1 15.5 1 15.5

BMI = body mass index (P / T2)

4.2 / Main criteria

The criterion of effectiveness retained is the reduction of 5% of the LGL between D0 and D56. A chi-square test has been performed, it shows a significant difference at p = 0.006. Table 2: Loss of thickness between the treated group and the placebo group

Verum placebo

Evolution at D28 of the ultrasound thickness of the LGL in% Average (standard deviation) - 5.54% (5.06) + 0.61% (2.09)

Minimum - 0.19% + 3.84%

Maximum - 20.92 - 4.66%

Evolution on D56 of the ultrasound thickness of the LGL in%

Mean (standard deviation) - 8.90% (9.05) - 0.85% (4.33)

Minimum - 0.15% + 5.39%

Maximum - 39.03% - 13.10%

These means are significantly different between the verum and the placebo.

4.3 / Secondary criteria

There is a significant difference (p <0.05) between the two groups in the assessment of the development of cellulite, on the effectiveness of the product, the firmness of the skin, the reduction in the number and depth of quilt ", as well as the feeling of wearing fitted clothes.

Table 3: Questionnaire by visual analog scale at D28

Verum placebo

Did the gel you used seem effective?

Mean (standard deviation) 7.20 (2.57) 4.82 (3.32)

Minimum 1.3 0.0

Maximum 11.2 11.9

Table 4: Questionnaires by visual analog scale on D56

Verum placebo

Did the gel you used seem effective overall? Mean (standard deviation) 9.17 (3.34) 5.54 (3.99)

Minimum 2.7 0.6

Maximum 14.1 13.9

Did you find it effective in reducing dimples (number and depth)?

Mean (standard deviation) 8.68 (3.52) 5.14 (4.28)

Minimum 1.9 0.0

Maximum 14.2 14.3 Did it seem effective on the firmness of your skin?

Mean (standard deviation) 9.93 (3.05) 6.74 (4.81)

Minimum 3.6. 0.4

Maximum 14.1 14.9

Do you feel like you are wearing your tight-fitting clothes better?

Mean (standard deviation) 9.76 (3.74) 5.80 (5.13)

10 Minimum 2.8 0, ^' 0

Maximum 14.9 14.8

These subjective analog questionnaires are consistent with the measurements made.

15

The daily leaves show an improvement in the smoothness of the skin, as well as its suppleness.

4.4 / Tolerance

^• 20

Reports of itching or tingling at the point of application are negligible. The rare reports are rated 1/3, short-lived, they were spontaneously resolved and did not suggest stopping treatment. No reports concern redness.

.25

Vital parameters are not significantly modified by nicotine gel.

4.5 / Satisfaction

30

Patient satisfaction was assessed using an analog scale. There is a significant difference in responses between the two groups, both on D28 and D56. Table 5: 'Would you recommend this gel'? "

Verum placebo

D28

Mean (standard deviation) 9.60 (3.62) 7.09 (4.13)

Minimum 1.0 0.0

Maximum 14.9 15

D56

Mean (standard deviation) 12.11 (2.38) 7.11 (5.27)

Minimum 7.9 1.3

Maximum 15.0 14.9

There is an increase in the mean of the satisfaction index and an increase in the significance between the two groups between D28 (p = 0.044) and D56 (p = 0.006).

5 / DISCUSSION

Nicotine, used in low doses, acts directly on localized gynoid lipodystrophy, more commonly called cellulite, by significantly reducing its thickness (by 8.9% on average). The entire study population lost weight (-1.37 Kg in the verum group, compared to -0.71 Kg in the placebo group). There is no significant difference between these two groups for this criterion, neither at D28, nor at D56, nor by noting the variation. The free nicotine used in this study therefore does not show an overall weight loss effect. We therefore conclude that the effect of nicotine is localized and not systemic. The change in the thickness of cellulite is therefore not attributable to the weight loss noted in the two groups.

The patients noted that the nicotinic gel was effective overall to reduce the importance of their cellulite, reduce the number and depth of the dimples. This development is noticeable with the wearing of fitted clothing. Finally, the effect of nicotine gel on firmness, tone and smoothness of the skin is noted.

Patient tolerance and satisfaction is good.

Note the concordance of the measured results, the analog visual scale patient assessments and the satisfaction index.

Example 2: Formulation

Slimming gel g% g

Ethyl alcohol 95c 45

Isopropyl alcohol 5

Carbopol 980 2

Glycerol 10

Propylene glycol 10

Trolamine 0.3

Nicotine base (pm = 162.23g) 0.03

Water qs 100.00

Slimming balm g% g

Natural ozokerite 15.00

Liquid purcellin oil 10

White vaseline 15

Trolamine 0.5

Nicotine base (pm = 162.23g) 0.03

QS Curator

Antioxidant QS

Vaseline oil qs 100,000 Thermo-slimming body oil g% g

Hexyl Nicotinate 3

“Miglyol 812 (fatty acid triglycerides) from the company DYNAMIT NOBEL 15

Isopropyl palmitate 10

Sweet almond oil 8

Trolamine 0.5

Nicotine base (pm = 162.23g) 0.03

QS Curator

QS fragrance

Antioxidant QS

Vaseline oil qs 100,000

Firming foam g% g

Cationic polymer "CELQUAT L-200" from the company NATIONAL STARCH 2

Surfactant (TWEEN 20) 3

Oxyethyenated nonyphenol (12 moles of ethylene oxide) 10

Trolamine 0.5

Nicotine base (pm = 162.23g) 0.03

Glycerin 5

QS Curator

Ethyl alcohol qs 100.00

This composition is intended to be packaged in an aerosol in the presence of a propellant, butane for example.

Anti-wrinkle cream g% g

Glycerol stearate 0.5

Polysorbate 60 ("T een 60" sold by ^* the company ICI 0.5

Stearic acid 4

Triethanolamine 3

Resveratrol 3

Nicotine base (pm = 162.23g) 0.03

Carbomer 4

Shea butter 15 Perhydrosqualene 15

QS fragrance

QS Curator

Water qs 100,000

Oil-in-water emulsion prepared conventionally for those skilled in the art.

Anti-orange peel cream g% g

Trolamine 0.5

Nicotine base (pm = 162.23g) 0.03

Sodium dimethicone copolyol acetyl methyltaurate

(Pecosil DCT from PHOENIX) 5 mineral oil 15

Glycerin 5

QS fragrance

QS Curator

Water qs 100,000

Oil-in-water emulsion prepared in a conventional manner for a person skilled in the art.

Claims

1 / Topical cosmetic composition comprising nicotine in mixture with at least one cosmetically acceptable vehicle, characterized in that the nicotine is free nicotine.

2 / Composition according to Claim 1, characterized in that the free nicotine represents between 0.001 and 0.5% by weight of the composition

3 / Composition according to one of the preceding claims, characterized in that it is in the form of gel, oily gel, cream, ointment, milk, lotion, balm, spray, emulsion, patch, stick.

4 / Use of the composition according to one of the preceding claims to reduce or limit any localized fatty overload, in particular of the cellulite type.

5 / Use of the composition according to one of claims 1 to 3 to improve the firmness of the epidemic.

61 Use of the composition according to one of claims 1 to 3 for combating skin aging.

11 Use of the composition according to one of claims 1 to 3 to improve the sweetness of the epidemic.

8 / A method of cosmetic treatment of local fatty overloads of the cellulite type in particular, according to which an effective amount of the composition object of one of claims 1 to 3 is applied locally, topically. 9 / A method according to claim 8, characterized in that the amount of nicotine released is between 0.3 and 3 mg per application.